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Purposes We present the first in-human brain PET imaging data of the new α4β2 nicotinic acetylcholine receptor (nAChR)–targeting radioligand (+)-[18F]Flubatine. Aims were to develop a kinetic modeling-based approach to quantify (+)-[18F]Flubatine and compare the data of healthy controls (HCs) and patients with Alzheimer’s disease (AD); to investigate the partial volume effect (PVE) on regional (+)-[18F]Flubatine binding; and whether (+)-[18F]Flubatine binding and cognitive test data respective β-amyloid radiotracer accumulation were correlated. Methods We examined 11 HCs and 9 mild AD patients. All subjects underwent neuropsychological testing and [11C]PiB PET/MRI examination. (+)-[18F]Flubatine PET data were evaluated using full kinetic modeling and regional as well as voxel-based analyses. Results With 270-min p.i., the unchanged parent compound amounted to 97 ± 2%. Adequate fits of the time-activity curves were obtained with the 1 tissue compartment model (1TCM). (+)-[18F]Flubatine distribution volume (binding) was significantly reduced in bilateral mesial temporal cortex in AD patients compared with HCs (right 10.6 ± 1.1 vs 11.6 ± 1.4, p = 0.049; left 11.0 ± 1.1 vs 12.2 ± 1.8, p = 0.046; one-sided t tests each). PVE correction increased not only (+)-[18F]Flubatine binding of approximately 15% but also standard deviation of 0.4–70%. Cognitive test data and (+)-[18F]Flubatine binding were significantly correlated in the left anterior cingulate, right posterior cingulate, and right parietal cortex (r > 0.5, p 18F]Flubatine binding and [11C]PiB standardized uptake value ratios were negatively correlated in several regions; whereas in HCs, a positive correlation between cortical (+)-[18F]Flubatine binding and [11C]PiB accumulation in the white matter was found. No adverse event related to (+)-[18F]Flubatine occurred. Conclusion (+)-[18F]Flubatine is a safe and stable PET ligand. Full kinetic modeling can be realized by 1TCM without metabolite correction. (+)-[18F]Flubatine binding affinity was high enough to detect group differences. Of interest, correlation between white matter β-amyloid PET uptake and (+)-[18F]Flubatine binding indicated an association between white matter integrity and availability of α4β2 nAChRs. Overall, (+)-[18F]Flubatine showed favorable characteristics and has therefore the potential to serve as α4β2 nAChR–targeting PET ligand in further clinical trials.

Acute pain serves as a protective mechanism that alerts us to potential tissue damage and drives a behavioural response that removes us from danger. The neural circuitry critical for mounting this behavioural response is situated within the brainstem and is also crucial for producing analgesic and hyperalgesic responses. In particular, the periaqueductal grey, rostral ventromedial medulla, locus coeruleus and subnucleus reticularis dorsalis are important structures that directly or indirectly modulate nociceptive transmission at the primary nociceptive synapse. Substantial evidence from experimental animal studies suggests that plasticity within this system contributes to the initiation and/or maintenance of chronic neuropathic pain, and may even predispose individuals to developing chronic pain. Indeed, overwhelming evidence indicates that plasticity within this circuitry favours pro-nociception at the primary synapse in neuropathic pain conditions, a process that ultimately contributes to a hyperalgesic state. Although experimental animal investigations have been crucial in our understanding of the anatomy and function of the brainstem pain-modulation circuitry, it is vital to understand this system in acute and chronic pain states in humans so that more effective treatments can be developed. Recent functional MRI studies have identified a key role of this system during various analgesic and hyperalgesic responses including placebo analgesia, offset analgesia, attentional analgesia, conditioned pain modulation, central sensitisation and temporal summation. Moreover, recent MRI investigations have begun to explore brainstem pain-modulation circuitry plasticity in chronic neuropathic pain conditions and have identified altered grey matter volumes and functioning throughout the circuitry. Considering the findings from animal investigations, it is likely that these changes reflect a shift towards pro-nociception that ultimately contributes to the maintenance of neuropathic pain. The purpose of this review is to provide an overview of the human brain imaging investigations that have improved our understanding of the pain-modulation system in acute pain states and in neuropathic conditions. Our interpretation of the findings from these studies is often guided by the existing body of experimental animal literature, in addition to evidence from psychophysical investigations. Overall, understanding the plasticity of this system in human neuropathic pain conditions alongside the existing experimental animal literature will ultimately improve treatment options.

The successes of magnetic resonance imaging and modern optical imaging of human brain function have stimulated the development of complementary modalities that offer molecular specificity, fine spatiotemporal resolution, and sufficient penetration simultaneously. By virtue of its rich optical contrast, acoustic resolution, and imaging depth far beyond the optical transport mean free path (∼1 mm in biological tissues), photoacoustic computed tomography (PACT) offers a promising complementary modality. In this article, PACT for functional human brain imaging is reviewed in its hardware, reconstruction algorithms, in vivo demonstration, and potential roadmap.

Schizophrenia is a heterogeneous and poorly understood mental disorder that is presently defined solely by its behavioral symptoms. Advances in genetic, epidemiological and brain imaging techniques in the past half century, however, have significantly advanced our understanding of the underlying biology of the disorder. In spite of these advances clinical research remains limited in its power to establish the causal relationships that link etiology with pathophysiology and symptoms. In this context, animal models provide an important tool for causally testing hypotheses about biological processes postulated to be disrupted in the disorder. While animal models can exploit a variety of entry points towards the study of schizophrenia, here we describe an approach that seeks to closely approximate functional alterations observed with brain imaging techniques in patients. By modeling these intermediate pathophysiological alterations in animals, this approach offers an opportunity to (1) tightly link a single functional brain abnormality with its behavioral consequences, and (2) to determine whether a single pathophysiology can causally produce alterations in other brain areas that have been described in patients. In this review we first summarize a selection of well-replicated biological abnormalities described in the schizophrenia literature. We then provide examples of animal models that were studied in the context of patient imaging findings describing enhanced striatal dopamine D2 receptor function, alterations in thalamo-prefrontal circuit function, and metabolic hyperfunction of the hippocampus. Lastly, we discuss the implications of findings from these animal models for our present understanding of schizophrenia, and consider key unanswered questions for future research in animal models and human patients.

Third harmonic generation microscopy (THG) was used for high-resolution label-free human brain imaging. The THG images of human brain tissues show neuronal soma, dendrites, and lipofuscin in gray matter while myelinated axons in white matter.

Over the last two decades, developments of human brain stroke imaging have raised several questions about the place of new MRI biomarkers in the acute management of stroke and the prediction of poststroke outcome. Recent studies have demonstrated the main role of perfusion-weighted imaging in the identification of the best cerebral perfusion profile for a better response after reperfusion therapies in acute ischemic stroke. A major issue remains the early prediction of stroke outcome. While voxel-based lesion-symptom mapping emphasized the influence of stroke location, the analysis of the brain parenchyma underpinning the stroke lesion showed the relevance of prestroke cerebral status, including cortical atrophy, white matter integrity, or presence of chronic cortical cerebral microinfarcts. Moreover, besides the evaluation of the visually abnormal brain tissue, the analysis of normal-appearing brain parenchyma using diffusion tensor imaging and magnetization transfer imaging or spectroscopy offered new biomarkers to improve the prediction of the prognosis and new targets to follow in therapeutic trials. The aim of this review was to depict the main new radiological biomarkers reported in the last two decades that will provide a more thorough prediction of functional, motor, and neuropsychological outcome following the stroke. These new developments in neuroimaging might be a cornerstone in the emerging personalized medicine for stroke patients.

The tropomyosin receptor kinase TrkA/B/C family is responsible for human neuronal growth, survival, and differentiation from early nervous system development stages onward. Downregulation of TrkA/B/C receptors characterizes numerous neurological disorders including Alzheimer's disease (AD). Abnormally expressed Trk receptors or chimeric Trk fusion proteins are also well-characterized oncogenic drivers in a variety of neurogenic and non-neurogenic human neoplasms and are currently the focus of intensive clinical research. Previously, we have described the clinical translation of a highly selective and potent carbon-11-labeled pan-Trk radioligand and the preclinical characterization of the optimized fluorine-18-labeled analogue, [18F]TRACK, for in vivo Trk positron emission tomography (PET) imaging. We describe herein central nervous system selectivity assessment and first-in-human study of [18F]TRACK.

BACKGROUND: Mobile computed tomography (CT) with a cone-beam source is increasingly used in the clinical field. Mobile cone-beam CT (CBCT) has great merits; however, its clinical utility for brain imaging has been limited due to problems including scan time and image quality. OBJECTIVE: The aim of this study was to develop a dedicated mobile volumetric CBCT for obtaining brain images, and to optimize the imaging protocol using a brain phantom. METHODS: The mobile volumetric CBCT system was evaluated with regards to scan time and image quality, measured as signal-to-noise-ratio (SNR), contrast-to-noise-ratio (CNR), spatial resolution (10% MTF), and effective dose. Brain images were obtained using a CT phantom. RESULTS: The CT scan took 5.14 s at 360 projection views. SNR and CNR were 5.67 and 14.5 at 120 kV/10 mA. SNR and CNR values showed slight improvement as the x-ray voltage and current increased ( p< 0.001). Effective dose and 10% MTF were 0.92 mSv and 360 µm at 120 kV/10 mA. Various intracranial structures were clearly visible in the brain phantom images. CONCLUSIONS: Using this CBCT under optimal imaging acquisition conditions, it is possible to obtain human brain images with low radiation dose, reproducible image quality, and fast scan time.

Molecular and functional imaging techniques have been used and combined with pharmacological probes to evaluate the role of dopamine in impulsivity. Overall, strong evidence links striatal dopaminergic function with impulsivity, measured by self-reports and laboratory tests of cognitive control and reward-based decision-making. The combination of molecular imaging using positron emission tomography (PET) with functional magnetic resonance imaging (fMRI) specifically implicates striatal D2-type dopamine receptors (i.e., D2 and D3) and corticostriatal connectivity in cognitive control. Low levels of striatal and midbrain D2-type receptor availability correlate with self-reported impulsivity, whereas striatal D2-type receptor availability shows positive correlation with motor response inhibition and cognitive flexibility. Impulsive choice on reward-based decision-making tasks also is related to deficits in striatal D2-type dopamine receptor availability, and there is evidence for an inverted U-shaped function in this relationship, reflecting an optimum of striatal dopaminergic activity. Findings from studies of clinical populations that present striatal dopamine D2-type receptor deficits as well as healthy control research participants identify D2-type receptors as therapeutic targets to improve cognitive control.

Using the α7-nAChR radiotracer, [(18)F]ASEM, we present the first successful human positron emission tomography (PET) studies. Rodent occupancy with three clinically employed α7-nAChR drugs confirms the specificity of the radiotracer.Five healthy male subjects were imaged for 90 min following IV [(18)F]ASEM. Two subjects were scanned for the second time (test/retest; TRV). Mouse biodistribution of [(18)F]ASEM was carried out in CD1 mice injected with using human equivalent doses of DMXB-A, EVP-6124, and varenicline to block specific binding.[(18)F]ASEM readily entered the brain and peaked at 15 min post-injection with reversible kinetics and a peak %SUV of about 400 %. The regional human brain distribution of [(18)F]ASEM matched previous in vitro data and baboon PET results. The precuneus, parietal, occipital, cingulate cortexes, putamen, and thalamus showed high values of distribution volume (20 ml/ml) and binding potentials1 with TRV averaged 10.8 ± 5.1 %. In mouse distribution studies, there was significant dose-dependent blockade in the mouse brain with DMXB-A as well as the other two α7-nAChR drugs.The characteristics of [(18)F]ASEM are consistent with the ability to quantify α7-nAChR in the human brain. [(18)F]ASEM is suitable for imaging neuropsychiatric disorders and target engagement (receptor occupancy) of potential α7-nAChR drugs.

PURPOSE: Recently a new MR endogenous contrast mechanism was reported. It allows specifically imaging the magnetization transfer (MT) effect arising from inhomogeneously broadened components of the NMR spectrum, and was hence dubbed ihMT. Such unique NMR lineshape properties are presumably occurring in myelin because of its specifically ordered, multilayered sheath structure. Here, optimization of a pulsed ihMT preparation module is presented to provide guidance for future studies and improve the understanding of underlying contrast mechanisms. METHODS: This study was performed at 1.5 Tesla on healthy volunteers. A pulsed ihMT preparation was implemented in combination with a HASTE readout module. The pulse width, interpulse repetition time, total saturation duration and RF saturation power were considered for optimization of the ihMT sensitivity and contrast. RESULTS: An optimal configuration of the preparation module was derived, leading to 10% ihMT signal in internal capsule (relative to unsaturated data) and around 200% signal increase relative to gray matter, i.e., approximately 10-fold superior contrast compared with conventional MT ratios, measured under similar experimental conditions. CONCLUSION: Overall the ihMT sequence was robust, sensitive and very specific for white matter. These findings suggest great potential for assessing brain myelination and for better characterization of myelin related disorders. Magn Reson Med 73:2111-2121, 2015. © 2014 Wiley Periodicals, Inc.

This paper proposes YURAGI synthesis for brain imaging under the skull. The advantage of the proposed method over conventional methods is that, using YURAGI synthesis, it is possible to obtain the effective results without image registration. Image registration is generally needed when more than two images are to be synthesized into one image. YURAGI synthesis does not need image registration; thus, its method is simpler than other methods that need image synthesis. The effectiveness of the proposed method was confirmed by comparing its error rate and accuracy with those of other methods. YURAGI leads the simple and energy-saving system with performing autoregulation. Autoregulation is utilized in many biological systems. In this study, YURAGI was applied to an ultrasound-based diagnostic medical imaging technique. The experimental results using YURAGI were superior to those using othermethods. Thus, YURAGI is useful for visualizing the human brain.11. This paper has been reviewed and accepted as a regular paper. The paper was invited and incorporated into the Special Issue on Advances in Fuzzy Inference and its Related Techniques.

The introduction of hybrid positron emission/magnetic resonance tomography (PET/MR) in diagnostic clinical imaging was a major step in the evolution of ever-more sophisticated imaging systems combining two strategies formerly regarded as technically incompatible in a single device. The advent of PET/MR opened up many new avenues in clinical and research environments, mainly by providing multi-modality images obtained during a single examination. Ideally, simultaneous data acquisition with hybrid PET/MR should warrant exact image co-registration of all multi-modality image volumes provided by both systems. This assumes that there is negligible mutual electronic, technical and logistical interference on the respective simultaneous measurements. Recently, such hybrid dedicated head and whole-body systems were successfully applied in an increasing number of cases. When employed for brain imaging, PET/MR has the potential to provide high-resolution multi-modality datasets. However, it also demands careful consideration of the multitude of features offered, as well as the limitations. There are open issues that have to be considered, such as the handling of patient motion during extended periods of data acquisition, optimized sampling of derived images to ease the visual interpretation and quantitative evaluation of co-registered images. This paper will briefly summarize the current status of PET/MR within the framework of developments for image co-registration and discuss current limitations and future perspectives.

Diffusion-weighted magnetic resonance imaging (DW-MRI) provides a novel insight into the brain to facilitate our understanding of the brain connectivity and microstructure. While in-vivo DW-MRI enables imaging of living patients and longitudinal studies of brain changes, post-mortem ex-vivo DW-MRI has numerous advantages. Ex-vivo imaging benefits from greater resolution and sensitivity due to the lack of imaging time constraints; the use of tighter fitting coils; and the lack of movement artifacts. This allows characterization of normal and abnormal tissues with unprecedented resolution and sensitivity, facilitating our ability to investigate anatomical structures that are inaccessible in-vivo. This also offers the opportunity to develop today novel imaging biomarkers that will, with tomorrow’s MR technology, enable improved in-vivo assessment of the risk of disease in an individual. Post-mortem studies, however, generally rely on the fixation of specimen to inhibit tissue decay which starts as soon as tissue is deprived from its blood supply. Unfortunately, fixation of tissues substantially alters tissue diffusivity profiles. In addition, ex-vivo DW-MRI requires particular care when packaging the specimen because the presence of microscopic air bubbles gives rise to geometric and intensity image distortion. In this work, we considered the specific requirements of post-mortem imaging and designed an optimized protocol for ex-vivo whole brain DW-MRI using a human clinical 3T scanner. Human clinical 3T scanners are available to a large number of researchers and, unlike most animal scanners, have a bore diameter large enough to image a whole human brain. Our optimized protocol will facilitate widespread ex-vivo investigations of large specimen.

Autism spectrum disorders include a heterogeneous collection of conditions characterized by the syndrome of autism, namely, marked impairments in social interaction and communication and a markedly restricted and peculiar range of interests and activities. Neuroscience research on autism spectrum disorders is hindered by various different definitions utilized by contributors over the past century. Currently, the criteria for autism spectrum disorders are in flux; new diagnostic requirements for autism spectrum disorders have just been promulgated. Autism spectrum disorders include autistic disorder, Asperger syndrome, Heller syndrome, Rett syndrome, fragile X syndrome, and pervasive developmental disorders. The Rett syndrome is associated with mutations in the X-linked methyl-CpG-binding protein 2 located at the Xq28 region. Fragile X syndrome is associated with abnormalities in the X chromosome. With the exception of the Rett syndrome and the fragile X syndrome, there are likely multiple etiologies for the other autism spectrum disorders. Thus, autism spectrum disorders likely include conditions with disparate biological causes. Human brain imaging includes a spectrum of tools to identify both the structure and the function of the human nervous system utilizing a variety of energy sources and detection modalities. Anomalies in the physiology of the frontal and temporal lobes characterize subgroups of people with autism spectrum disorders. Dysfunction of the frontal and temporal lobes likely provides a pathophysiological basis for the social and language deficits characteristic of the disorders. Dysfunction of the serotonergic and cholinergic systems has been identified in subgroups of people with autism spectrum disorders to support the hypotheses that these systems play a role in the pathophysiology of autism spectrum disorders. Conflicting and contradictory results from reports on human brain imaging of autism spectrum disorders likely stem from the differences in the diagnostic tools, imaging procedures, participant populations, and other characteristics of individual investigations. Additionally, the small sample sizes employed in many imaging studies lack the power to establish a statistical significance. Future research to investigate the brain imaging of humans with autism spectrum disorders can be facilitated by the utilization of accurate diagnostic criteria and rating instruments. Additionally, the identification of demographic, educational, psychiatric, psychological, and neurological characteristics may help to classify people with autism spectrum disorders according to useful clinical groups. Investigation of genetic markers for particular neurotransmitters likely altered in autism spectrum disorders may lead to the discovery of genetic mutations characteristic of subgroups. Careful research including the spectrum of investigative tools will likely result in the identification of biological markers to identify distinct groups such as the Rett syndrome and fragile X syndrome.

By enabling visualization of physiological processes, “Functional imaging,” broadly defined, has dramatically enhanced our ability to explore and better understand human neuroscience and human disease. fMRI has become the keystone of a broad array of functional imaging methods that are revealing the links between brain and behavior in normal and pathological states. Very high strength magnets and advanced large N phased-array coils now enable ultra-high spatial and temporal resolution MRI and fMRI, while advances in MR gradient coil technology have improved our ability to assess tissue microstructure and connectivity almost an order of magnitude. Beyond MRI, positron emission tomography (PET) imaging provides the means to map neurochemical events with exquisite sensitivity, and recent work suggests the potential to extend neurochemical mapping towards quantification of receptor trafficking, and measurements of metabolism and neurotransmitter release dynamics on time frames of a few minutes; tomographic op...

Adenosine is an endogenous modulator of various physiological functions mediated by adenosine receptors (ARs). Advances in radiotracer chemistry have led to the development of novel imaging probes for ARs, especially adenosine A 1 and A 2A receptors. In this review, we discuss (1) functions of adenosine and ARs in the central nervous system; (2) brain imaging for ARs, including postmortem studies and positron emission tomography; (3) comparison of radioligands for AR imaging in health and diseases; and (4) kinetic analysis for quantitative AR imaging.

Anger is among one of the basic human emotions underlying human behavior. Here, we review the neuroimaging studies of anger, specifically those studies investigating the subjective experience of anger as well as the perception of anger. In addition, we review the findings from studies in patient populations with an increased propensity for anger. Finally, we relate the research on neural correlates of anger to the research on aggression and violence.

The use of whole post-mortem human brain hemispheres for the studies of the biochemical neuroanatomy is described. Cryosections prepared from whole hemispheres have been successfully used for in vitro radioligand autoradiography, in situ hybridization histochemistry and histochemistry. Functional autoradiography using 5-HT 1A receptor stimulated [ 35 S]GTP &#110 S binding and volume rendering of images from radioligand autoradiography to describe the distribution of D 2 /D 3 dopamine receptors in three dimensions are also discussed. A detailed characterization of the biochemical neuroanatomy of several neuronal components can thus be obtained simultaneously in all regions in the normal and diseased brain, resulting in an extensive information on the human brain morphology and biochemistry.

Nicotinic acetylcholinergic receptors (nAChR's) have been implicated in several brain disorders, including addiction, Parkinson's disease, Alzheimer's disease and schizophrenia. Here we report in vitro selectivity and functional properties, toxicity in rats, in vivo evaluation in humans, and comparison across species of [18 F]Nifene, a fast acting PET imaging agent for α4β2* nAChRs. Nifene had subnanomolar affinities for hα2β2 (0.34 nM), hα3β2 (0.80 nM) and hα4β2 (0.83 nM) nAChR but weaker (27-219 nM) for hβ4 nAChR subtypes and 169 nM for hα7 nAChR. In functional assays, Nifene (100 μM) exhibited 14% agonist and >50% antagonist characteristics. In 14-day acute toxicity in rats, the maximum tolerated dose (MTD) and the no observed adverse effect level (NOAEL) were estimated to exceed 40 μg/kg/day (278 μg/m2 /day). In human PET studies, [18 F]Nifene (185 MBq; 15% than males. No significant aging effect was observed in [18 F]Nifene binding over 5 decades. In all species (mice, rats, monkeys, and humans) thalamus showed highest [18 F]Nifene binding with reference region ratios >2 compared to extrathalamic regions. Our findings suggest that [18 F]Nifene PET may be used to study α4β2* nAChRs in various CNS disorders and for translational research.

The introduction of combination antiretroviral therapy (cART) has significantly decreased the severity of HIV-associated neurocognitive disorder (HAND) and increased the life expectancy of the human immunodeficiency virus (HIV) positive population. Nevertheless, patients still show persistent neurocognitive disorders due to associated structural and functional brain changes. The purpose of this chapter is to highlight the significance of brain neuroimaging techniques and biomarkers in understanding the pathophysiology related to HIV infection and HAND. These imaging modalities include volumetric (MRI), magnetic resonance spectroscopy (MRS), positron emission tomography (PET), single-photon emission computed tomography (SPECT), diffusion tensor imaging (DTI), arterial spin labeling (ASL), and perfusion MRI. The authors predict that with neuroimaging advances at the molecular level, it will soon be the noninvasive gold standard in brain pathology diagnosis.

The authors obtained brain images with patients in the upright position using a newly designed and constructed vertical MR system. They found little gravitational effect on brain structures, even in the case of a severely atrophied brain. Their vertical system was practical for routine clinical usage and might provide information regarding gravitational effects on regional perfusion and other aspects of brain physiology.

With the advent of neuroreceptor and neurotransmission imaging by means of positron emission tomography and single-photon emission computed tomography in vivo, it is now possible to directly record the normal and pathophysiological processes served by monoamines in the brain, as well as to examine the possibilities and potential impact of treatment of disorders of monoaminergic neurotransmission. This article describes the methods of noninvasive brain imaging and the benefits that this imaging can bring to the understanding of disturbed monoaminergic neurotransmission, the mechanisms underlying the disturbances, and the impact of possible therapies.

The increasing appreciation of neuroradiologists, other healthcare professionals, neuroscientists, and cognitive scientists for the exquisite detail of anatomical, physiological, and functional magnetic resonance imaging (fMRI) of the human brain has encouraged increasing use of MRI in medical care and research. As MRI has no adverse biological effects when performed within FDA guidelines, longitudinal studies of development and aging and detailed studies through repetitive measurements on single subjects can be undertaken with insignificant risk. Scanner performance for clinical MR scanners has been enhanced as field strengths have migrated upward to 3.0 Tesla. It is appropriate to consider the technical challenges of further improving sensitivity by moving from 3.0 to 9.4T, the highest magnetic field scanner now available for human MRI that became operational in 2004.

The serotonergic system plays a key modulatory role in the brain and is the target for many drug treatments for brain disorders either through reuptake blockade or via interactions at the 14 subtypes of 5-HT receptors. This review provides the history and current status of radioligands used for positron emission tomography (PET) and single photon emission computerized tomography (SPECT) imaging of human brain serotonin (5-HT) receptors, the 5-HT transporter (SERT), and 5-HT synthesis rate. Currently available radioligands for in vivo brain imaging of the 5-HT system in humans include antagonists for the 5-HT(1A), 5-HT(1B), 5-HT(2A), and 5-HT(4) receptors, and for SERT. Here we describe the evolution of these radioligands, along with the attempts made to develop radioligands for additional serotonergic targets. We describe the properties needed for a radioligand to become successful and the main caveats. The success of a PET or SPECT radioligand can ultimately be assessed by its frequency of use, its utility in humans, and the number of research sites using it relative to its invention date, and so these aspects are also covered. In conclusion, the development of PET and SPECT radioligands to image serotonergic targets is of high interest, and successful evaluation in humans is leading to invaluable insight into normal and abnormal brain function, emphasizing the need for continued development of both SPECT and PET radioligands for human brain imaging.

Appetite and body weight regulation are controlled by the central nervous system (CNS) in a rather complicated manner. The human brain plays a central role in integrating internal and external inputs to modulate energy homeostasis. Although homeostatic control by the hypothalamus is currently considered to be primarily responsible for controlling appetite, most of the available evidence derives from experiments in rodents, and the role of this system in regulating appetite in states of hunger/starvation and in the pathogenesis of overeating/obesity remains to be fully elucidated in humans. Further, cognitive and affective processes have been implicated in the dysregulation of eating behavior in humans, but their exact relative contributions as well as the respective underlying mechanisms remain unclear. We briefly review each of these systems here and present the current state of research in an attempt to update clinicians and clinical researchers alike on the status and future directions of obesity research.

Parkinson's disease (PD) is a neurodegenerative disorder resulting from progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta. Therefore, imaging of the SN has been regarded to hold greatest potential for use in the diagnosis of PD. At the 7.0T magnetic resonance imaging (MRI), it is now possible to delineate clearly the shapes and boundaries of the SN. We scanned eight early and two advanced PD patients, along with nine age-matched control subjects, using a 7.0T MRI in an attempt to directly visualize the SN and quantify the differences in shape and boundaries of SN between PD subjects in comparison with the normal control subjects. In the normal controls, the boundaries between the SN and crus cerebri appear smooth, and clean "arch" shapes that stretch ventrally from posterior to anterior. In contrast, these smooth and clean arch-like boundaries were lost in PD subjects. The measured correlation analyses show that, in PD patients, there is age-dependent correlation and substantially stronger UPDRS motor score-dependent correlation. These results suggest that, by using 7.0T MRI, it appears possible to use these visible and distinctive changes in morphology as a diagnostic marker of PD.

P-glycoprotein (P-gp) is a membrane-bound efflux pump that limits the distribution of drugs to several organs of the body. At the blood-brain barrier, P-gp blocks the entry of both loperamide and its metabolite, N-desmethyl-loperamide (N-dLop), and thereby prevents central opiate effects. Animal studies have shown that (11)C-dLop, compared with (11)C-loperamide, is an especially promising radiotracer because it generates negligible radiometabolites that enter the brain. The purposes of this study were to determine whether (11)C-dLop is a substrate for P-gp at the blood-brain barrier in humans and to measure the distribution of radioactivity in the entire body to estimate radiation exposure.Brain PET scans were acquired in 4 healthy subjects for 90 min and included concurrent measurements of the plasma concentration of unchanged radiotracer. Time-activity data from the whole brain were quantified using a 1-tissue-compartment model to estimate the rate of entry (K(1)) of radiotracer into the brain. Whole-body PET scans were acquired in 8 healthy subjects for 120 min.For brain imaging, after the injection of (11)C-dLop the concentration of radioactivity in the brain was low (standardized uptake value, approximately 15%) and stable after approximately 20 min. In contrast, uptake of radioactivity in the pituitary was about 50-fold higher than that in the brain. The plasma concentration of (11)C-dLop declined rapidly, but the percentage composition of plasma was unusually stable, with the parent radiotracer constituting 85% of total radioactivity after approximately 5 min. The rate of brain entry was low (K(1) = 0.009 +/- 0.002 mL.cm(-3).min(-1); n = 4). For whole-body imaging, as a measure of radiation exposure to the entire body the effective dose of (11)C-dLop was 7.8 +/- 0.6 muSv/MBq (n = 8).The low brain uptake of radioactivity is consistent with (11)C-dLop being a substrate for P-gp in humans and confirms that this radiotracer generates negligible quantities of brain-penetrant radiometabolites. In addition, the low rate of K(1) is consistent with P-gp rapidly effluxing substrates while they transit through the lipid bilayer. The radiation exposure of (11)C-dLop is similar to that of many other (11)C-radiotracers. Thus, (11)C-dLop is a promising radiotracer to study the function of P-gp at the blood-brain barrier, at which impaired function would allow increased uptake into the brain.

Fear extinction is the decrease in conditioned fear responses that normally occurs when a conditioned stimulus (CS) is repeatedly presented in the absence of the aversive unconditioned stimulus (US). Extinction does not erase the initial CS-US association, but is thought to form a new memory. After extinction training, extinction memory competes with conditioning memory for control of fear expression. Deficits in fear extinction are thought to contribute to post-traumatic stress disorder (PTSD). Herein, we review studies performed in rats showing that the medial prefrontal cortex plays a critical role in the retention and expression of extinction memory. We also review human studies indicating that prefrontal areas homologous to those critical for extinction in rats are structurally and functionally deficient in patients with PTSD. We then discuss how findings from rat studies may allow us to: (1) develop new fear extinction paradigms in humans, (2) make specific predictions as to the location of extinction-related areas in humans, and (3) improve current extinction-based behavioral therapies for anxiety disorders.

Over the past decade, functional neuroimaging has contributed greatly to our knowledge about the neuropharmacology of substance misuse in man. Techniques such as functional magnetic resonance imaging, positron emission tomography (PET) or single photon emission tomography (SPET) can measure changes in regional cerebral activity, whereas changes in neuropharmacological parameters (e.g. receptor number and neurotransmitter levels) can be directly measured only with PET and SPET. Recently, a series of studies have shown common effects of substances of misuse on the brain, such as an acute increase in dopamine release (followed by hypofunction after chronic use) and cue exposure-induced activation of the frontal cortex, as well as specific effects, such as ecstasy-induced decreases in serotonergic transporters and occupancy of opiate receptors by substitute drugs (e.g. methadone and buprenorphine) in opiate addicts.

There are numerous methods designed to monitor brain neuropathologies resulting from a wide arsenal of insults. Regardless of the cause of neuronal death, reactive glial cells always appear at and around the site of degeneration. These cells are distinguished by the exceptional abundance of peripheral benzodiazepine receptors, particularly compared with surrounding neurons. Measuring the binding of specific ligands to these peripheral benzodiazepine receptors offers a unique indirect marker for reliable damage assessment in the CNS and a faithful indicator for the accompanying cognitive deficits.

Recent functional imaging studies with neuropsychological measures suggest that several brain regions, which are related to dopamine (DA) neurotransmission, would be included among candidates of the major neural underpinnings of affective and cognitive functions such as pleasure and reward processing. Furthermore, evidence suggests the association of the pathophysiologies of neuropsychiatric illnesses such as schizophrenia and Parkinson's disease with the dysregulation of DA-related neurotransmission in these brain regions. Positron emission tomography (PET) is a non-invasive in-vivo imaging tool for measuring DA neurotransmission. We hereby review the evidence of human D1R function, focusing on its associations with cognitive functions including working memory, emotional processing and decision-making, as well as the pathologies of psychiatric illnesses, while introducing our D1R PET imaging studies. Although D1R dysfunction would not always be regarded as a direct cause of the disorders, that is to say, it would not be disease-specific, it might be related to the pathophysiologies by influencing cognitive functions of the individuals. In this sense, the evidence in D1R dysfunction might provide a new insight into the mechanisms of the symptoms of neuropsychiatric disorders and lead to the development of new ways of their dimensional classifications.

Imaging of tardive dyskinesia (TD) was for years limited to the anatomical evaluation of the striatum with the use of computed tomography and had eventually moved to the superior anatomical information offered by magnetic resonance imaging. More recently, however, it was demonstrated that functional imaging of dopamine (DA) transporter through the use of single-photon emission computed tomography or of the different steps in DA metabolism through the use of positron emission tomography can shed more light on the assessment of patients with TD.

Medications acting on central nervous system (CNS) opioid receptors (ORs) continue to be prevalent in the worldwide market of analgesics for the treatment of chronic pain. However, the discovery, development, and attainment of regulatory approval of novel, safe, and effective medications and formulations for this indication, which lack abuse potential, have been extremely difficult. To advance proof-of-concept studies determining receptor occupancy mechanisms of action and appropriate dosing, pharmacokinetics, and targeted pharmacodynamics for which candidate medications are being tested, it is possible in healthy human volunteers and patient populations to conduct nuclear imaging, such as quantitative positron emission tomography (PET) imaging of major OR types (mu (μ), delta (δ), and kappa (κ)) in the CNS. This review discusses the emerging opportunities enabled by these brain imaging tools, with examples of studies utilizing PET radiotracers, to identify drug targets and biomarkers in order to accelerate drug discovery and development, and to further the understanding of the role of CNS ORs in the areas of pain and substance use disorder treatment research.

Disrupted-in-Schizophrenia 1 (DISC1) is a well researched candidate gene for schizophrenia and affective disorders with a range of functions relating to neurodevelopment. Several human brain imaging studies investigating correlations between common and rare variants in DISC1 and brain structure and function have shown conflicting results. A meta-analysis of case/control data showed no association between schizophrenia and any common SNP in DISC1. Therefore it is timely to review the literature to plan the direction of future studies. Twenty-two human brain imaging studies have examined the influence of DISC1 variants in health, schizophrenia, bipolar disorder or depression. The most studied common SNPs are Ser704Cys (rs821616) and Leu607Phe (rs6675281). Some imaging-genomic studies report effects on frontal, temporal and hippocampal structural indices in health and illness and a volumetric longitudinal study supports a putative role for these common SNPs in neurodevelopment. Callosal agenesis is described in association with rare deletions at 1q42 which include DISC1 and rare sequence variants at DISC1 itself. DISC1 interactions with translin-associated factor X (TRAX) and neuregulin have been shown to influence several regional volumes. In the first study involving neonates, a role for Ser704Cys (rs821616) has been highlighted in prenatal brain development with large clusters of reduced grey matter reported in the frontal lobes. Functional MRI studies examining associations between Ser704Cys (rs821616) and Leu607Phe (rs6675281) with prefrontal and hippocampal activation have also given inconsistent results. Prefrontal function was reported to be associated with interaction between DISC1 and CITRON (CIT) in health. Preliminary magnetic resonance spectroscopy and diffusion tensor data support the influence of Ser704Cys (rs821616) status on grey and white matter integrity. The glutamate system remains uninvestigated. Associations between rare sequence variants and structural changes in brain regions including the corpus callosum and effects of gene-gene interactions on brain structure and function are promising areas for future study.

The selective nature of human perception and action implies a modulatory interaction between sensorimotor processes and attentional processes. This paper explores the use of functional imaging in humans to explore the mechanisms of perceptual selection and the fate of irrelevant stimuli that are not selected. Experiments with positron emission tomography show that two qualitatively different patterns of modulation of cerebral blood flow can be observed in experiments where non–spatial visual attention and auditory attention are manipulated. These patterns of modulation of cerebral blood flow modulation can be described as gain control and bias signal mechanisms. In visual and auditory cortex, the dominant change in cerebral blood flow associated with attention to either modality is related to a bias signal. The relation of these patterns of modulation to attentional effects that have been observed in single neurons is discussed. The existence of mechanisms for selective perception raises the more general question of whether irrelevant ignored stimuli are nevertheless perceived. Lavie‘apos; theory of attention proposes that the degree to which ignored stimuli are processed varies depending on the perceptual load of the current task. Evidence from behavioural and functional magnetic resonance imaging studies of ignored visual motion processing is presented in support of this proposal.

We recently developed a novel cannabinoid subtype-1 (CB1) receptor radioligand (11)C-SD5024 for brain imaging. This study aimed to evaluate (11)C-SD5024 both in vitro and in vivo and compare it with the other CB1 receptor ligands previously used in humans, i.e., (11)C-MePPEP, (11)C-OMAR, (18)F-MK-9470, and (18)F-FMPEP-d2. In vitro experiments were performed to measure dissociation constant (Ki) in the human brain and to measure the lipophilicity of the five CB1 receptor ligands listed above. In vivo specific binding in monkeys was measured by comparing total distribution volume (VT) at baseline and after full receptor blockade. The kinetics of (11)C-SD5024 in humans were evaluated in seven healthy subjects with compartmental modeling. SD5024 showed Ki=0.47nM, which was at an intermediate level among the five CB1 receptor ligands. Lipophilicity (LogD7.4) was 3.79, which is appropriate for brain imaging. Monkey scans showed high proportion of specific binding: ~80% of VT. In humans, (11)C-SD5024 showed peak brain uptake of 1.5-3 standardized uptake value, which was slightly higher than that of (11)C-OMAR and (18)F-MK-9470. One-compartment model showed good fitting, consistent with the vast majority of brain uptake being specific binding found in the monkey. Regional VT values were consistent with known distribution of CB1 receptors. VT calculated from 80 and 120min of scan data was strongly correlated (R(2)=0.97), indicating that 80min provided adequate information for quantitation and that the influence of radiometabolites was low. Intersubject variability for VT of (11)C-SD5024 was 22%, which was low among the five radioligands and indicated precise measurement. In conclusion, (11)C-SD5024 has appropriate affinity and lipophilicity, high specific binding, moderate brain uptake, and provides good precision to measure the binding. The results suggest that (11)C-SD5024 is slightly better than or equivalent to (11)C-OMAR and that both are suitable for clinical studies, especially those that involve two scans in one day.

This chapter describes the study of tinnitus in humans by means of neuroimaging to measure brain function and structure. Here, “neuroimaging” is defined to mean any of a variety of noninvasive techniques, from scalp recordings of electrical activity, to images permitting quantification of the gray and white matter of the cerebral cortex, to neurally coupled changes in blood flow. This chapter focuses specifically on the use of neuroimaging to understand chronic, subjective tinnitus, that is, tinnitus that is lasting and cannot be explained by either an external sound source, or a source within the body (Eggermont and Zeng, Chapter 1). Although defined as the perception of sound lacking a physical sound source, the clinical condition of tinnitus is more than the percept. The tinnitus patient often presents with depression, anxiety, difficulties concentrating, and/or difficulties sleeping. These nonperceptual aspects of the condition are what make tinnitus a clinical problem for approximately 5–10% of the population (Coles, 1984; Shargorodsky et al., 2010).

OBJECTIVE: The mesocoelic recess (MCR) is found in the brain of human embryos and fetuses. The mesocoelic recess seems to be functionally related to the subcommissural organ that is one of neurosecretory organs involved in osmoregulation on the basis of data from other species. Subsequently, recent speculation as to the importance of the subcommissural organ in the development of congenital hydrocephalus has been raised. Yet unlike other mammals, MCR is known to be a vestigial structure in the adult human brain. Here, we performed the in vivo imaging identification of this space to investigate functional and clinical correlations. METHODS: We studied adult human brains using a 7.0-T magnetic resonance imaging (MRI). Twenty healthy individuals aged 22 to 30 years were selected, and they were all volunteers. The parasagittal images through the intercommissural line were examined. We determined the type of shape of the MCR; a triangular C shape was classified as type 1, and a trapezoidal concave shape was classified as type 2. RESULTS: In 14 brains, the recesses were radiologically demonstrated just rostral to the tectal plate of the midbrain and covered the ventral aspect of the posterior commissure and pointed the opening into the aqueduct. The average size of the circumference of the MCR measured from the end point of the C-shaped cup was 6.82 mm. CONCLUSIONS: This study on the anatomy of the MCR of adult brains in vivo is the first of its kind, thanks to the availability of 7.0-T MRI because it has been barely discernible even in autopsy specimens as well as in radiology owing to the resolution limit of the currently available imaging system. The current study raises awareness of the MCR, an important but little-known anatomic structure in adult human brain. This visualization of MCR in human in vivo with ultrahigh-field MRI will certainly provide us important clues including the functional information of MCR, a mystery of modern neurological science.

Assorted technologies such as; EEG, MEG, fMRI, BEM, MRI, TMS and BCI are being integrated to understand how human visual cortical areas interact during controlled laboratory and natural viewing conditions. Our focus is on the problem of separating signals from the spatially close early visual areas. The solution involves taking advantage of known functional anatomy to guide stimulus selection and employing principles of spatial and temporal response properties that simplify analysis. The method also unifies MEG and EEG recordings and provides a means for improving existing boundary element head models. In going beyond carefully controlled stimuli, in natural viewing with scanning eye movements, assessing brain states with BCI is a most challenging task. Frequent eye movements contribute artifacts to the recordings. A linear regression method is introduced that is shown to effectively characterize these frequent artifacts and could be used to remove them. In free viewing, saccadic landings initiate visual processing epochs and could be used to trigger strictly time based analysis methods. However, temporal instabilities indicate frequency based analysis would be an important adjunct. The class of Cauchy filter functions is introduced that have narrow time and frequency properties well matched to the EEG/MEG spectrum for avoiding channel leakage.

Because subjective tinnitus is typically localized to the ear with hearing loss, tinnitus was traditionally thought to originate from neural hyperactivity in the damaged ear. However, most studies have found that hearing loss reduces the neural outputs from the damaged cochlea. These negative findings led to the hypothesis that tinnitus arises from aberrant neural activity in the central auditory system. Positron emission tomography imaging studies performed on tinnitus patients that could modulate their tinnitus provide evidence showing that the aberrant neural activity that gives rise to tinnitus resides in the central auditory pathway. To investigate the biological basis of tinnitus in more detail, an animal model was developed that allowed behavioral measures of tinnitus to be obtained from individual rats after inducing tinnitus with high doses of salicylate or high-intensity noise. This behavioral model was used to test the efficacy of memantine, an N-methyl-D-aspartate antagonist, and scopolamine, an anticholinergic, in suppressing salicylate-induced tinnitus. Neither drug completely suppressed salicylate-induced tinnitus. To detect the physiological changes associated with tinnitus, chronic microwire electrodes were implanted in the auditory cortex and measurements were obtained from the auditory cortex before and after salicylate and noise exposures known to induce tinnitus. High doses of salicylate or high-level noise exposure generally resulted in sound-evoked hyperactivity in the electrophysiological responses recorded from the auditory cortex of awake-animals. However, anesthetic tended to suppress or abolish the hyperactivity.

Two eight-channel MRI receive-only coils were developed to provide whole-brain coverage at 1.5 T and 3.0 T field strength, respectively. Objectives were an image signal-to-noise ratio superior to standard designs throughout the human brain, as well as high parallel imaging performance. Electromagnetic field simulations were used to determine array diameter and inter-element coil gap. Low mutual inductive coupling was achieved at 1.5 and 3.0 T using high-impedance pre-amplifiers. Coils show an average SNR improvement over commercial birdcage coils of 2.4 and 2.3 for the 1.5 T and 3.0 T design, respectively. The mean of the noise-amplification factor related to reconstruction of under-sampled data (g-factor) was 1.03 for 2-fold under-sampled data (rate-2) and 1.22 for rate-3 at 1.5 T. For data acquired with the 3.0 T coil array, these values were respectively 1.06 for rate-2 and 1.37 for rate-3.